Diabetes mellitus (DM) comprises a series of disorders, all characterized by hyperglycemia. Type I (“insulin dependent”) DM is characterized by insulin deficiency, whereas Type II (“non-insulin dependent” or “adult-onset”) DM is characterized by insulin resistance, impaired insulin secretion, and increased hepatic glucose production. Chronic complications of DM result from hyperglycemia and include retinopathy, neuropathy, nephropathy, and cardiovascular disease.
In the pancreatic β-cell, membrane depolarization and an oscillatory increase in [Ca2+]i are key features in glucose-induced insulin secretion. The oscillatory increase in [Ca2+]i is regulated by a sophisticated interplay between nutrients, hormones and neurotransmitters and is due to both Ca2+ influx through voltage-gated L-type Ca2+ channels and Ca2+ mobilization from intracellular stores such as the endoplasmic reticulum (ER) (Berggren & Larsson 1994, Biochem. Soc. Transact. 22:12-18). Upon metabolism of glucose within the β-cell, ATP is formed, which in turn closes specific ATP-regulated K+ channels, triggering depolarization of the plasma membrane. Such depolarization leads to an opening of voltage-gated L-type Ca2+ channels, Ca2+ influx, an increase in [Ca2+]i, and subsequently insulin release. The opening of the voltage-gated L-type Ca2+ channels thus occurs at glucose concentration levels that stimulate pancreatic beta cells to secrete insulin.
L-type Ca2+ channels are multi-subunit proteins, consisting of a combination of α, β, and γ subunits, where each type of subunit exists in multiple forms. While the α1 subunit forms the pore of the L-type Ca2+ channel, the β subunits are believed to play a key role in the assembly/expression of the channel complex, and to modulate Ca2+ currents through the β1 subunits (Singer et al. 1991, Science 253:1553-1557; Hullin et al. 1992, EMBO J. 11:885-890; Tareilus et al. 1997, Proc. Natl. Acad. Sci. USA 94:1703-1708). To date the role of Ca2+ channel β subunits in insulin secretion has mainly been studied by heterologous expression experiments (Ihara et al. 1995, Mol. Endocrinol. 9:121-130). Pancreatic β-cells express both β2 and β3 subunits.
Intracellular stores such as the ER are able to modulate depolarization-induced Ca2+ signaling by sequestering some of the Ca2+ entering through the voltage-gated L-type Ca2+ channels into intracellular calcium stores, or by releasing additional Ca2+ into the cytoplasm. Such Ca2+ release may occur through Ca2+ mediated activation of phosphatidylinositol-specific phospholipase C (PI-PLC) and formation of inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) or through direct gating of the intracellular Ca2+ channels by the incoming Ca2+.
Most efforts to develop drugs to promote insulin secretion, treat insulin resistance, and increase the efficiency of glucose homeostasis have targeted the ATP-regulated K+ channels. However, such drugs often act regardless of the blood glucose concentration, and thus can lead to serious side effects, such as hypoglycemia. Therefore, there is a need in the art to identify targets for therapeutics that do not suffer from these drawbacks.